MeCP2 Governs Maternal Hyperandrogenism-Induced Cortical Defects and Autism-like Behaviors via Noncanonical AR-Dependent Regulation of Mef2c

Elevated androgen levels during pregnancy have been associated with an increased occurrence of several neurodevelopmental disorders in offspring, including autism spectrum disorder (ASD) and intellectual disability. Nevertheless, the precise mechanisms through which androgens affect brain development remain poorly comprehended. By employing a prenatal hyperandrogenic mouse model, we observed abnormal cerebral cortex development and autism-like behaviors predominantly in male offspring, effects could be prevented by an androgen receptor (AR) blocker. Mechanistically, we identify the transcription factor MEF2C as a critical downstream target of androgen signaling in cortical neurogenesis. Remarkably, AR-mediated transcriptional upregulation of Mef2c occurs independently of canonical androgen response elements (AREs). Instead, AR interacts with MeCP2 and co-occupies the MeCP2 binding site within the Mef2c gene promoter region. Knocking down Mecp2 could also reverse the effects of hyperandrogen on cortical neurogenesis. Moreover, MeCP2 duplication upregulated the MEF2C level and cortical neurogenesis in male offspring without prenatal hyperandrogen exposure, and knocking down Mef2c or blocking AR both could restore the effects of MeCP2 duplication on cortical neurogenesis in male offspring without prenatal hyperandrogen exposure. Collectively, our results elucidated a MeCP2-dependent non-ARE regulation pathway under androgen in cortical development.